A multifaceted study for the development of new antitumor nucleosides and nucleotides is proposed, which takes cognisance of the two fundamental requirements of current cancer chemotherapy: 1) The immediate need for new chemotherapeutic agents, and 2) The long-range necessity for a rational foundation for such therapy. The first objective is approached through the preparation of new nucleoside and nucleotide analogs, and through the study of their antitumor activity, their parmacological properties, and their modes of action. This aim also includes an evaluation of the antitumor actitivity of these compounds in combination with other agents, which have the capacity to enhance their selectivity according to our concepts of metabolic conditioning and metabolic actuation. The second objective is approached through a detailed study of the role which cyclic nucleotides, and specifically cyclic CMP, play in the regulation of tumor cell growth. Based upon our recent isolation of biologically active cyclic CMP from tumor cells, we propose to study the biosynthetic path leading to the formation of cyclic CMP; the presence of specific phosphodiesterases in various tumor and normal tissues; the phase in the cell cycle at which the nucleotide acts; the relation of cyclic CMP to cell transformation; the concentration of cyclic CMP in various tumors as compared to normal tissues; the effect of cyclic CMP on cellular cyclic AMP and cyclic GMP concentrations; and, finally, its effect upon selected enzymes, particularly in relation to the action of various hormones. BIBLIOGRAPHIC REFERENCES: M. Bobek and A. Bloch: Synthesis and Biological Activity of 5-Fluoro-4'-thiouridine and Some Related Nucleosides. J. Med. Chem. 18, 784, 1975. C. Coutsogeorgopoulos, A. Bloch, K. A. Watanabe and J. J. Fox: Inhibitors of Protein Synthesis. 4. Studies on the Structure-Activity Relationship of Gougerotin and Some of Its Analogs. J. Med. Chem. 18, 771, 1975.